Thursday, 31 May 2012

The following are the slides from my talk that I gave today at the Association of British Neurologists (ABN) meeting in Brighton. The purpose of the meeting was to challenge consultant neurologists to think about the services they provide MSers. I hope I achieved something.

With the sad failure of the CUPID trial for Progressive MSers, we can't just wait for 3-5 years for each trial to occur. We need novel designs that can speed up this process!

With this in mind please take the time to do the "MS lumbar puncture" survey, which may help get one such design off the ground (Click on Top left) or here for the link to the study design. It does not matter if you are RRMS your view is still important.

BACKGROUND: Brain atrophy (shrinkage) is a well-accepted imaging biomarker of multiple sclerosis (MS) that partially correlates with both physical disability and cognitive impairment.

METHODOLOGY/PRINCIPAL FINDINGS: Based on MRI scans of 60 MS cases and 37 healthy volunteers, we measured the volumes of white matter (WM) lesions, cortical gray matter (GM), cerebral WM, caudate nucleus, putamen, thalamus, ventricles, and brainstem using a validated and completely automated segmentation method. We correlated these volumes with the Expanded Disability Status Scale (EDSS), MS Severity Scale (MSSS), MS Functional Composite (MSFC), and quantitative measures of ankle strength and toe sensation. Normalized volumes of both cortical and subcortical GM structures were abnormally low in the MS group, whereas no abnormality was found in the volume of the cerebral WM. High physical disability was associated with low cerebral WM, thalamus, and brainstem volumes (partial correlation coefficients ∼0.3-0.4) but not with low cortical GM volume. Thalamus volumes were inversely (the smaller the volume the more lesions) correlated with lesion load (r = -0.36, p<0.005).

CONCLUSION:The GM is atrophic in MS. Although lower WM volume is associated with greater disability, as might be expected, WM volume was on average in the normal range. This paradoxical result might be explained by the presence of co-existing pathological processes, such as tissue damage and repair, that cause both atrophy and hypertrophy and that underlie the observed disability.

This study reports that in MS the grey matter is shrinking indicating nerve loss. In the white matter disability was correlated with white matter shrinkage, however the volume of the white matter was not that different from that found in healthy people. However the volume of the white matter can be artificially heightened by swelling and tissue scarring and so can mask the damage that is occurring. MS is affecting both grey and white matter.This study lends further credence that monitoring grey matter changes may be a better way to monitor progression.

BACKGROUND: Although the impact of stigma has been highlighted for epileptic populations, the experiences of people living with other neurological conditions have been less well studied.

PURPOSE: In order to promote research on stigma among people with neurological conditions, the investigators sought to develop and psychometrically validate an 8-item questionnaire measuring internalised and enacted stigma experienced by people with epilepsy, MS, Parkinson's disease (PD), stroke and amyotrophic lateral sclerosis (ALS).

METHOD: They used item response theory methodologies to select items and field tested their items with 587 participants from eight academic medical centres across the USA.

RESULTS: They conducted exploratory and confirmatory factor analysis as well as examined the scale's reliability and validity. In addition, they conducted an analysis of variance test to examine mean total score differences across the five neurological conditions. Data from people across conditions revealed that the shortened instrument conformed to an essentially unidimensional model of multifaceted stigma as a one-factor questionnaire with correlated residuals on a pair of items that distinctly measured internalised stigma.

CONCLUSION: Preliminary evidence suggests that the Stigma Scale for Chronic Illness 8-item version fits a unidimensional model, which assesses enacted and internalised stigma, and has adequate internal consistency/reliability and validity in relation to psychological distress and patient performance. Their results suggest fairly low stigma for neurological populations. In addition, their results suggest that stigma may be more severe for patients with ALS relative to those with MS and PD. In the future, the SSCI-8 scale could be used practically in clinic settings to examine stigma without the patient burden associated with lengthier scales.

"Stigma (plural: stigmata) is a word that originally means a "sign", "point", or "branding mark". Social stigma is the severe disapproval of, or discontent with, a person on the grounds of characteristics that distinguish them from other members of a society. Stigma is an important issue as it does affect MSers social and occupational functioning, which is why a lot of MSers prefer to remain in the "closet", i.e. they don't want others to know about their disease. There is no doubt that MSers are stigmatised in particular when it comes to employment and insurance issues. What can we do about it? De-stigmatising a disease is all about education; educating individuals with the disease and society in general."

BACKGROUND AND PURPOSE: CCSVI has been reported to occur at high frequency in MS. Its significance in relation to MR imaging parameters also needs to be determined, both in patients with MS and HCs. Therefore, this study determined the associations of CCSVI and conventional MR imaging outcomes in patients with MS and in HCs.

MATERIALS AND METHODS: T2, T1, and gadolinium lesion number, LV, and brain atrophy were assessed on 3T MR imaging in 301 subjects, of whom 162 had RRMS, 66 had secondary-progressive MS subtype, and 73 were HCs. CCSVI was assessed using extracranial and transcranial Doppler evaluation. The MR imaging measure differences were explored with 27 borderline cases for CCSVI, added to both the negative and positive CCSVI groups to assess sensitivity of the results of these cases.

RESULTS: No significant differences between subjects with and without CCSVI were found in any of the individual diagnostic subgroups or MS disease subtypes for lesion burden and atrophy measures, independently of the CCSVI classification criteria used, except for a trend for higher T2 lesion number (irrespective of how borderline cases were classified) and lower brain volume (when borderline cases were included in the positive group) in patients with RRMS with CCSVI. No CCSVI or MR imaging differences were found between 26 HCs with, or 47 without, a familial relationship.

CONCLUSIONS: CCSVI is not associated with more severe lesion burden or brain atrophy in patients with MS or in HCs.

The debate regarding the possible link between chronic cerebrospinal venous insufficiency and multiple sclerosis
(MS) is continuously becoming more and more contentious due to the
current lack of level 1 evidence from randomized trials. Regardless of
this continued uncertainty surrounding the safety and efficacy of this
therapy, MS patients from Canada, and other jurisdictions, are traveling
abroad to receive central venous angioplasty and, unfortunately, some
also receive venous stents. They often return home with few instructions
regarding follow-up or medical therapy. In response we propose some
interim, practical recommendations for post-procedural surveillance and
medical therapy, until further information is available.

BACKGROUND: Chronic cerebrospinal venous insufficiency
(CCSVI) is a vascular condition characterized by anomalies of the
primary veins outside the skull that has been reported to be associated
with MS. In the blinded Combined Transcranial (TCD) and Extracranial
Venous Doppler Evaluation (CTEVD) study, we found that prevalence of
CCSVI was significantly higher in multiple sclerosis
(MS) vs. healthy controls (HC) (56.1% vs. 22.7%, p < 0.001). The
objective was to evaluate the clinical correlates of venous anomalies
indicative of CCSVI in patients with MS

METHODS: The
original study enrolled 499 subjects; 163 HC, 289 MS, 21 CIS and 26
subjects with other neurological disorders who underwent a clinical
examination and a combined Doppler and TCD scan of the head and neck.
This analysis was restricted to adult subjects with MS (RRMS: n = 181,
SP-MS: n = 80 and PP-MS: n = 12). Disability status was evaluated by
using the Kurtzke Expanded Disability Status Scale (EDSS) and MS
severity scale (MSSS).

This work aims to present a broad magnetic resonance imaging (MRI) protocol for use in the study of chronic cerebrospinal venous insufficiency (CCSVI). They cite that low total flow in the 2 dominant veins seemed to be the strongest indicator for risk of having blockage or thinnign of the vessel in the MS population.

Communicating the diagnosis of MS is a challenging task, often undertaken with discomfort by most neurologists. Only a few studies have investigated MSers satisfaction with timing and way of receiving the diagnosis, but surveys regarding physicians' attitude towards diagnosis disclosure are even more limited. The goal of this work was to highlight Italian neurologists' behavioral and emotional approach to MSers, making them sensitive to their difficulties and to the importance of an empathic relationship. The majority of Italian neurologists participating in this study have a good perception of their ability to manage this difficult communicating process and believe in the great effect this moment may have on a life-long disease experience. Improving communication skills may help the therapeutic alliance, enhancing MSers acceptance of the disease, as well as motivation and adherence to treatment disclosing the diagnosis of multiple sclerosis.

"An interesting article. From experience of talking to many MSers is that their experiences vary wildly. Some have had good experiences and others very poor. What has yours been?"

Methods: Peripheral blood T cells from NMOers and HC were examined for recognition of AQP4 and production of proinflammatory cytokines. Monocytes were evaluated for production of T cell-polarizing cytokines and expression of costimulatory molecules.

Results: T cells from NMOers and HC proliferated to intact AQP4 or AQP4 peptides. T cells from NMOers demonstrated greater proliferation to AQP4 than HC, and responded most vigorously to peptide residues 61-80 (p61-80), a naturally processed (is formed by the natural breakdown on the protein) immunodominant determinant of intact AQP4. T cells were CD4+, and corresponding to association of NMO with HLA-DRB1*0301 and DRB3, AQP4 p61-80-specific T cells were HLA-DR-restricted. The T cell epitope within AQP4 p61-80 was mapped to 63-76, which contains ten residues with 90% homology to a sequence within Clostridium perfringens ABC transporter permease. T cells from NMOers proliferated to this homologous bacterial sequence and cross-reactivity between it and self-AQP4 was observed, supporting molecular mimicry. In NMO, AQP4 p61-80-specific T cells exhibited Th17 polarization, and furthermore, monocytes produced more IL-6, a Th17-polarizing cytokine, and expressed elevated CD40 and CD80 costimulatory molecules, suggesting innate immunologic dysfunction.

Interpretation: AQP4-specific T cell responses are amplified in NMO, exhibit a Th17 bias and display cross-reactivity to a protein of an indigenous intestinal bacteria, providing new perspectives for investigating NMO pathogenesis.

"This is a highly technical posting, but some of you may find it interesting in that it teaches us about the immune system and has relevance to MSers."

"Proteins are made up of a sequence of amino acids these are broken down by immune cells and loaded in to the major histocompatibility complex (MHC) as we previously described. T cells see their target proteins as a sequence of amino acids when loaded into the MHC. Some the of the amino acids anchor the peptides on to the MHC others face up and bind to the T cell receptor. Because of this some immune responses directed at bacterial and viral invaders can cross react with brain proteins as we discussed.

NMO is an MS-like disease that is associated with immune responses to a water channel that is predominantly located in astrocytes, an important cell in the brain. This study suggests that NMO could result from a cross-reactive immune response to gut bacteria. This would suggest that a course of anti-biotics could potentially influence NMO. Likewise it has been suggested previously that responses to EBV could cross-react with myelin responses in MS."

The T cell has a molecule that allows it to see its target. This is called the T cell receptor. There are many variants and this allows them to recognise alot (a billion billion) of targets

These come together so the T cell receptor recognises a linear sequence of amino acids and the MHC (=HLA).

There are twenty different amino acids that protiens are made from and T cells recognise 9-13 amino acids in a sequence. Some of the amino acids bind to the HLA and others bind to the T cell receptor. It is possible that a T cell that recognises a virus or bacteria could also react with a brain protein.

Each circle (above) is an amino acid the different colours represent different amino acids, white ones mean their identity are not important. Responses to Bacteria/virus 2 could cross-react with the brain protien. This is known as Molecular mimicry and is defined as the theoretical possibility that
sequence similarities between foreign and self-peptides are sufficient
to result in the cross-activation of autoreactive (autoimmune) T or B cells by pathogen-derived peptides.

Introduction: The CUPID study investigated the usefulness of cannabinoids (chemical compounds found in the cannabis plant) or THC slowing progression in MS.

Aims: The study set out to investigate the following:- 1. Does THC have any value in slowing progressive MS over a three year period? 2. Is THC safe over a three year period? 3. Can clinical trial design and conduct be improved by using newer methodology such as patient-based assessments (e.g. MS-specific questionnaires) rather than traditional testing or examination by doctors?

Participants and treatments: 493 MSers with primary or secondary progressive MS were recruited to the study from 27 centres across UK between May 2006 and July 2008. It was a requirement for participants entering the trial that their walking was affected by their MS but that they could still walk, with aids if necessary. Participants were randomly assigned to receive THC capsules or placebo (dummy) capsules, to be taken by mouth over a period of three years. 329 people were allocated to receive the THC capsules and 164 were allocated to the placebo group. For each participant, the first four weeks of the trial were devoted to establishing the best tolerated dose of study treatment. For the remainder of the study period, participants remained on a stable dose of trial treatment, as far as possible, before the dose was gradually reduced to zero at the end of the treatment period. The study was ‘double-blind’, meaning that neither the participants nor the doctors and nurses involved at the study sites knew which treatment group they were in. This is widely recognised as the ‘gold standard’ way to produce the most unbiased results in clinical trials.

Methods: The two ‘primary’ measures of treatment effectiveness used in the CUPID study were the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Impact Scale (MSIS-29). The MSIS-29 is a self-completion questionnaire specifically designed for MSers. Participants were asked to complete this every 6 months either in a paper-based form sent through the post, or via a web-based system on the computer. The study also collected information on a range of ‘secondary’ measures including a timed walk, peg test and number test (PASAT) which took place in the clinic. A variety of questionnaires were also used, to enable participants to provide their own assessment of their MS at regular intervals. At some centres, participants underwent yearly MRI scans to provide additional information.

Results: Overall the study found no evidence that THC has an effect on MS progression in either of the main outcomes (the EDSS neurological assessments conducted by doctors at the study clinics or the MSIS-29 questionnaire responses provided by the participants). The EDSS and MSIS-29 scores showed little change over the course of the study and no difference was found between the active and placebo groups. However, there was some evidence that THC might have a beneficial effect in participants at the lower end of the EDSS disability scale (i.e. in those participants whose MS was less advanced). As this benefit was only found in a small group of people rather than the whole study population, further studies will be needed to assess the robustness of this finding.

Interpretation: Although the study found no evidence that THC has an effect on MS progression, most study participants were at the high end of the disability scale at the start of the study and as a whole did not exhibit much change in their MS. There was some evidence from the two main study assessments (EDSS and MSIS-29) that participants with less disability had some slowing of MS progression but the number of people in this category was too small (in statistical terms) to conclude with certainty that THC is effective in slowing MS progression. More research will be needed to investigate these findings. One of the findings of the study was that the population of study participants did not deteriorate at the rate that had been expected. This is obviously good news and reflects well on the care now provided by the NHS for people with MS compared with previously. However, it does make it more difficult to identify any positive effects of trial treatment when the aim of treatment is to slow progression.

Developing treatments for progressive MS is complicated by the difficulty of designing and conducting clinical trials. In relapsing remitting MS, researchers can assess whether a treatment is reducing the number, frequency and severity of relapses, so measuring the effectiveness of treatments is more straightforward. It is much harder to evaluate the effectiveness of a treatment in progressive MS where symptoms worsen slowly over the course of months and years. This is partly because the measurement methods available to us do not necessarily capture disease progression accurately. The CUPID study is hugely important in terms of what MS researchers across the world will learn about conducting trials in progressive disease, so that we can continue to improve study design and the accuracy with which outcomes can be measured in both clinical practice and research.

"Professor Zajicek, colleagues, the MRC and study subjects must be congratulated on the completion of this study. It was a mammoth undertaking. We were hoping this study was going to be positive as it is based on a therapeutic strategy developed by MouseDoctor and MouseDoctor2 in their animal model of MS."

"It is now time to stop doing neuroprotective trials in progressive MS without using the putative neuroprotective agent in combination with an anti-inflammatory agent. PPMS and SPMS are inflammatory, the pathology studies in SPMS and PPMS are clear on this. THC is not anti-inflammatory, therefore this study did not address the inflammatory component of MS. The same criticisms apply to the lamotrigine SPMS study. I have been banging my head against the wall to get combination therapies neuroprotective studies done; may be the community will agree and reviewers' of grants will stop questioning the strategy."

"It would be tragedy if THC in combination with an anti-inflammatory worked in progressive MS. Have we killed THC off as a neuroprotective drug?"CoI: The Royal London Hospital was a site in this study and I was the local PI

Note from MouseDoctor.

With this failure we can't just wait for 3-5 year trials to occur, we need novel designs that can speed up this process! With this in mind please take the time to do the "MS lumbar puncture" survey which may help get one such design off the ground (Click on Top left)

Objective: The investigators sought to determine if vitamin D status is associated with developing new T2 lesions or contrast-enhancing lesions on brain MRI in relapsing MS.

Methods: EPIC is a 5-year longitudinal MS cohort study at the University of California, San Francisco. Participants had clinical evaluations, brain MRI, and blood draws annually. From the overall cohort, they evaluated MSers with clinically isolated syndrome or relapsing-remitting MS at baseline.

Interpretation: Vitamin D levels are inversely (lower the levels the worse MS) associated with MS activity on brain MRI. These results provide further support for a randomized trial of vitamin D supplementation.

"The other option is for MSers to make sure they vD replete; there are health benefits outside of MS to justify this approach, for example bone health, reduce your risks of infection to reduce your risks of certain tumours."

"The case for making sure the whole population is vD replete is very compelling; but then I would say that as I have a conflict of interest."

Objectives: Based on findings in animal models of autoimmune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic neuritis.

"erythropoietin is a hormone produced by the kidney that stimulates the bone marrow to make red blood cells. It has more recently been shown to have neuroprotective effects."Methods: MSers with optic neuritis were included
in this double-blind, placebo-controlled, phase II study
(ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups
receiving either 33,000IU recombinant human erythropoietin i.v. daily
for three days, or placebo, as an add-on therapy to methylprednisolone.
The primary outcome parameter was change in retinal nerve fibre layer
(RNFL) thickness after 16 weeks. Secondary outcome parameters included
optic nerve atrophy (loss of nerve cells) as assessed by MRI, changes in
visual acuity (how good your vision is), visual field (breadth of your
visual fields, and visual evoked potentials (VEPs, electrical tests of
how well the optic nerve conducts electrical impulses).

Results:
40 MSers were assigned into either treatment group (21/19
erythropoietin/placebo). Safety monitoring revealed no relevant issues.
37 MSers (20/17 erythropoietin/placebo) were analysed for the primary
endpoint according to the intention-to-treat protocol. RNFL thinning was
less apparent after erythropoietin treatment: Thickness of the RNFL
decreased by a median of 7.5μm by week 16 (mean±STD: 10.55±17.54μm)
compared to a median of 16.0μm (22.65±29.18μm) in the placebo group
(p=0.0357). Decrease in retrobulbar diameter of the optic nerve was
smaller in the erythropoietin group (p=0.0112). VEP latencies at week 16
were shorter in erythropoietin-treated patients than in the placebo
group (p=0.0011). Testing of visual functions revealed trends towards an
improved outcome after erythropoietin treatment.

Interpretation: These results give the first indications that erythropoietin might be neuroprotective in optic neuritis.

"We have been promoting optic neuritis as a model to demonstrate that treatments may be useful for progressive MS and have one compound in trial at the moment. This study uses a different drug called Erythropoietin. This is a growth factor that stimulates red blood cells and is sometimes used by unscrupulous atheletes who blood dope. However, as shown in animal studies it also has the potential to be neuroprotective. Therefore it may not only be of value of controlling retinal nerve loss in optic neuritis, but it also has the potential to control progressive MS. Although there are a number of clinical versions of EPO, there is also a variant that is neuroprotective (saves nerves from damage) but does not cause the production of red blood cells. This is really great news, but further studies will be needed to see if is really is useful for progressive MS and how it should be delivered as a therapeutic. This is a fantastic step in the right direction."

A New Note from Doctor M &M

"I would not like to be the devil's advocate but there are side-effects
associated with erythropoietin treatment. It should not be taken without medical
supervision".

"It is used in people with chronic kidney failure and other
situations with low red blood cells counts. As you may be aware, it has been
used as sports performance enhancers (doping).

The following information
is compiled from the Summary of Product Characteristics of erythropoietin. And
this is the very pure drug, not the one bought in the internet.

The
serious adverse drug reactions include venous and arterial thromboses and
embolism (that may have fatal outcomes), such as deep venous
thrombosis, pulmonary emboli, arterial thrombosis (including
heart attacks), retinal thrombosis. Strokes, both infarctions and
haemorrhages, and transient ischaemic attacks have also been reported.

There can be a dose-dependent increase in blood pressure or aggravation
of existing hypertension with need for close monitoring of the blood
pressure. Other common side-effects observed seizures, diarrhoea,
nausea, headache, flu-like illness, pyrexia,
rash and vomiting. Influenza-like illness including headaches,
arthralgia, myalgia, and pyrexia may occur especially at the start of treatment.

In all patients, haemoglobin levels should be closely monitored due
to a potential increased risk of thromboembolic events and fatal outcomes when
patients are treated at haemoglobin levels above the target for the indication
of use.

Hypersensitivity reactions, including cases of rash, urticaria,
anaphylactic reaction, and angioneurotic oedema have been reported. The most
severe side-effects seem to be hypertensive crisis with encephalopathy
and seizures, which are medical emmergencies.

Some companies have devised
erythropoietin derivatives that are tissue protective but do not
increase the numbers of red bloods cells".

THEREFORE DO NOT BE TEMPTED TO INVESTIGATE THE USE OF THIS DRUG, UNLESS AS PART OF AN APPROVED CLINICAL TRIAL

BACKGROUND: Fatigue in combination with gait and balance impairments can severely limit daily activities in MSers. Generalised fatigue has a major impact on walking ability, with moderately disabled
MSers experiencing difficulty in walking extended distances. Localised motor fatigue in the ankle dorsiflexors can lead to foot drop, further reducing functional ambulation. The aim of this study is to evaluate the effect of a simple dynamic dorsiflexion assist orthosis on walking-induced fatigue, gait, balance and functional mobility in
MSers.

METHODS: A randomised cross-over trial will be conducted with 40 community dwelling
MSers with mild to moderate mobility disability. Participants will initially be screened for disease severity, balance, strength, depression and fatigue at the South Australian Motion Analysis Centre. On two non-consecutive occasions, within two weeks, participants will undergo either the 6-minute walk test (6MWT) or the 6MWT while wearing a dorsiflexion ankle orthosis (with a randomised condition order). Distance walked, perceived exertion, perceived fatigue and the physiological cost of walking (the primary outcome measures) will be compared between the two walking conditions. Additional pre- and post-6MWT assessments for the two conditions will include tests of strength, reaction time, gait and balance.

DISCUSSION: This study will increase our understanding of motor fatigue on gait and balance control in
MSers and elucidate the effect of a Dynamic Ankle Orthosis on fatigue-related balance and gait in PWMS. It will also examine relationships between mobility and balance performance with perceived fatigue levels in this group.

"A publication about a planned study. Do you think it is well-designed? Would you change anything about the design? What about cost-effectiveness data? This study in the current form could not be used by NICE as it does not appear to include cost-effectiveness data. I would also want to know the impact on Dynamic Ankle Orthosis on falls and fractures. The latter is what our Commissioners' have asked us about Fampridine."

"These results speak for themselves. The greatest burden of MS is in the symptoms of neurological dysfunction it causes. This is not a definitive survey but gives you an idea of the mountain we need to climb to improve the lives of MSers. To be honest with you none of the treatments we have to target these symptoms is optimised at present; most are only partially effective and they come with significant side effects."

"What is interesting is the rating of these symptoms with fatigue, walking difficulties and pain topping the chart. Do you agree with this rating?"

Objectives: To evaluate SD and EDS in MSers and to test the reliability of subjective sleep questionnaires.

Methods: Demographic and clinical characteristics of unselected consecutive MSers were collected. Different questionnaires were used to assess quality of sleep, daytime sleepiness, fatigue, anxiety, depression and quality of life (QoL). Nocturnal polysomnography and Multiple Sleep Latency Test (MSLT) were performed in 25 selected MSers with fatigue and with or without EDS.

Results: 205 MSers were enrolled. More than half of the MSers were classified as 'poor sleepers'. In multivariate analysis, SD were correlated with disability, fatigue, depression, QoL, and pain, but not with EDS. Subjective sleepiness evaluated with the Epworth Sleepiness Scale and SD with the Pittsburgh Sleep Quality Index were not correlated with the results of the objective assessments of vigilance (MSLT) and sleep.

Conclusions: SD and EDS are frequent among MS patients. Objective assessment of vigilance and sleep can be challenging but MS patients who are poor sleepers should receive immediate assessment and treatment in order to improve QoL.

"Poor sleep hygiene and sleep disorders is another hidden disability in MS. Poor hygiene refers to bad habits, for example sleeping too much in the day, the inappropriate use of stimulants (caffeine, modafinil), no exercise, etc. Other factors that play a role is poor bladder function with nocturia (needing to pass urine at night), pain, spasms, restless legs, etc. I am beginning to realise that we need to take this issue a lot more seriously from a clinical perspective. I would be interested to know how many of you have a sleep disorder."

The extent of irreversible neuroaxonal (nerve cells and their processes) damage is the key determinant of permanent disability in traumatic and inflammatory conditions of the central nervous system (CNS). Structural damage is nevertheless in part compensated by neuroplastic events. However, it is unknown whether the same kinetics and mechanisms of neuroaxonal de- and regeneration take place in inflammatory and traumatic conditions. These investigators analysed neuroaxonal degeneration and plasticity in early MS lesions and traumatic brain injury (TBI). Neuroaxonal degeneration identified by the presence of SMI31+ neurons and SMI32+ axonal profiles were characteristic features of leukocortical TBI lesions (SMI is a staining technique to pick up damage axons). Axonal transport disturbances as determined by APP+ spheroids were present in both TBI and MS lesions to a similar degree. APP refers to amyloid precursor protein, which accumulates in bulbs and indicates that axons have been transected. Neurons expressing GAP43 and synaptophysin (Syn) were found under both pathological conditions. GAP43 and
synaptophysin are proteins that are produced at the synapse and are indicative of synaptic recovery. However, axonal swellings immunopositive for GAP43 and Syn clearly prevailed in subcortical MS lesions suggesting a higher regenerative potential in MS. In this context, GAP43+/APP+ axonal spheroid ratios correlated with macrophage infiltration in TBI and MS lesions supporting the idea that phagocyte activation might promote neuroplastic events. Furthermore, axonal GAP43+ and Syn+ swellings correlated with prolonged survival after TBI indicating a sustained regenerative response.

We have talked about neuro plasticity, by which damaged nerves form new connections to overcome the damage. The authors looked for SMI-32 expression, This is reacts with a nonphosphorylated (no phosphorous) epitope in neurofilament heavy chain a nerve protein of most mammalian species. This is often expressed by nerves in distress. Amyloid precursor protein (APP) is shuttled down the nerve and whenthe nerve is cut a stump forms and the APP being transported down the nerve accumulates in the stump and forms a bulb called a spheroid (round like a sphere). GAP43 a nerve growth protein found in the tips of growing nerve processes and synaptophysin another protein found around synapses of nerves. More of this was found in the MS lesions compared to the brain injury suggesting that they have a greater capacity to make new nerve connections in MS. This was associated with inflammation, namely macrophages that may be clearing damaged nerves and myelin. This suggests that the MS brain is plastic, and capable of recovery, as we have previously reported:Multiple Sclerosis Research: Research: Brain Plasticity16 Feb 2012

There is little agreement amongst neuropathologists regarding the timing and nature of oligodendrocyte loss in MS. The oligodendrocyte is the cell that makes myelin or the insulation around nerve fibres. This review describes changes that accompany acute oligodendrocyte loss in new MS lesions. Included is a description of the immunopathology of new lesions in 23 severe early cases selected from a bank of 300 MS autopsies. Oligodendrocytes in prephagocytic (before myelin debris is ingested by microglia) lesions exhibit cytopathic changes that include apoptosis (type of cell death) of oligodendrocytes immunoreactive for caspase 3 (an enzyme that triggers cell death), phagocytosis of apoptotic oligodendrocytes (ingestion of dead cells by microglia), swelling of cells with abnormal nuclei, complement deposition (proteins that damage cells), and lysis (popping of the cell membrane). These are non - specific changes that provide no clue as to the cause of oligodendrocyte injury. Associated changes include the presence of enlarged IgG + microglia and early macrophages, the presence nearby of a focus of inflammatory demyelination, an open blood brain barrier, and the presence of rare CD8 T cells (these are a type of white blood cell that mainly target viruses). Myelin contacted by IgG+ macrophages is immunoreactive for complement but not for IgG. It is likely that macrophage activity in evolving white and grey matter plaques is scavenging activity directed at non- vital myelin secondary to oligodendrocytes loss. One feature of MS that is not understood is the extraordinarily close resemblance the disease shows pathologically to neuromyelitis optica, including the fact that demyelination in both is secondary to a loss of caspase 3 - positive apoptotic oligodendrocytes. These similarities raise the possibility that like NMO, MS is an autoimmune disease in which oligodendrocyte apoptosis is determined by injury to some other glial or mesenchymal component.

With this in mind it is interesting that this pathology paper has been produced.

Objective: Neuromyelitis optica (NMO) and multiple sclerosis (MS) are considered inflammatory demyelinating diseases with distinguishing pathological characteristics. NMO pathology shows perivascular immunoglobulin G (IgG) and complement deposition, as well as an astrocytopathy (disease of astrocytes) with aquaporin-4 (AQP4) loss (aquaporins are channels that control water flow into cells). MS lesions reveal a profound, interindividual heterogeneity (different pathology between individuals) in immunopathological patterns of active demyelination,which has been challenged by the description of stage-dependent sequences of pathological features. The aim of our study was to compare the histological characteristics of early active demyelinating NMO and MS brain lesions.

Methods: 13 cases with supraspinal active demyelinating NMO lesions were analyzed using immunohistochemistry (technique for staining tissue). Results were compared with the published characteristics of MS lesions.

Results: A subset of supraspinal lesions (above the spinal cord, in other words from the brain) from AQP4 seropositive NMOers revealed both 1) complement deposition within macrophages at sites of active demyelination and 2) oligodendrocyte apoptosis and a preferential loss of myelin associated glycoprotein (MAG). These characteristics resemble features previously associated with both MS lesion patterns II and III (a classification system that was put forward by these authors 8 years ago), respectively and were present in addition to characteristic histopathological NMO features, namely AQP4 and astrocyte loss.

Interpretation: Early active demyelinating NMO lesions may show both complement deposition within macrophages and oligodendrocyte apoptosis associated with a selective loss of minor myelin proteins, in addition to typical NMO features. We hypothesize these features may occur simultaneously only in a subset of active demyelinating NMO lesions and the description by Barnett and Prineas should be re-evaluated. These observations could further support the concept of inter-individual heterogeneity in MS.

There are questions of whether NMO is MS, many say it is not but there are clearly overlaps. Was the idea that oligodendrocytes as the initial target for disease by Barnett and Prineas due to the study of NMO rather than MS?, but the central question is what drives the death of the oligos. Could it be a virus? Prof. G thinks so and John Prineas has hinted as this possibility in many of his talks. Only time will tell.

Objective: Pregnancy has a well documented effect on relapse risk in MS. Prospective studies have reported a significant decline by two-thirds in the rate of relapses during the third trimester of pregnancy and a significant increase by two-thirds during the first 3 months post-partum (after delivery). However, it is unclear as to whether there are any long term effects on disability.

Methods: Data were collated from clinical records and family histories systematically collected from the University of British Columbia MS Clinic.

Results: Clinical and term pregnancy data were available from 2105 female MSers. MSers having children after MS onset took the longest time to reach an Expanded Disability Status Scale (EDSS) score of 6 (mean 22.9 years) and MSers having children before MS onset were the quickest (mean 13.2 years). However, these effects were not related to term pregnancy and were fully accounted for by age of MS onset.

Conclusions: Pregnancy had no effect on the time to reach an EDSS score 6 (needing a unilateral walking aid; typically a stick). As MS predominantly affects women of childbearing age, women with MS can be reassured that term pregnancies do not appear to have any long-term effects on disability.

"A simple study with a definitive answer. This type of information is very useful when giving advice in clinic. Fertility and family planning advice is high up on the agenda of a most MSers, particularly as MS is a disease of young woman. I hope you find this information reassuring."

Regulation of the immune system may be part of the pathogenesis of relapsing-remitting MS (RRMS). In this study, the investigators demonstrate a dichotomy within the frequency of a regulatory white blood, cells called T-regs, among newly diagnosed RRMS MSers but not in healthy controls. A group of RRMS MSers was characterized by a significantly lower percentage of T-reg cells than that of their matched, healthy controls, and this was inversely correlated with their score on the EDSS. Since the EDSS reflected severity of the last attack, this study demonstrates a correlation between low frequency of T-reg cells and severity of clinical disease in RRMS.

This figure demonstrates the family of lineage of human T-cells and the immune messengers or cytokines that drives the development of these cells. T cell immunology is very complicated and these simple diagrams are not always proven to be correct. In reality there is a lot of overlap between different cells and their functions.

We have discussed what Th1 and Th2 T cells are in the past. For many years immunologists thought that the immune response was controlled by T suppressor cells, anergy, then Th2 and now the flavourof the month, or should I say years, are the T regulatory or T-reg cells. These cells are thought to prevent autoimmunity from occuring. These express a number of markers such as FoxP3 and CD25, which is the interleukin-2 receptor (which controls T cell growth). This study suggests that the healther the MSer is the less number of Tregs there are and so fits with dogma. If they could be induced then the idea is that it will inhibit disease. This is the mechanisms that most animal studies now show as a working mechanism...it wouldn't be dogma if people were not like lemmings and all find the same thing :-).

Daclizumab, a drug in phase 3 development for MS, blocks the action of CD25 as so you might think it would block T-reg function and make MS worse, but it appears to inhibit relapsing MS so quite the opposite. However, daclizumab's action appears to have nothing to do with T-regs and more to do with blocking the activation of T cells. Other mechanism may be by activating and expanding the numbers of the so called natural killer cells; these cells are important in fighting infections. Despite all these theories daclizumab appears to be effective in treating relapsing MS.

Previous studies have suggested an association between MS and infectious mononucleosis (IM) but data on the exact strength of this association or its selectivity have been conflicting. In this study the investigators evaluated the association between MS and a variety of common childhood infections and afflictions in a large population-based case-control study involving 2,877 MS cases and 2,673 controls in the Netherlands.

They examined the frequency of different common infections and afflictions before the age of 25 and the age at which they occurred, using a self-administered questionnaire. The Odds ratios (ORs) for the occurrence of a variety of clinically manifest common childhood infections including rubella, measles, chicken pox and mumps before the age of 25 for MSers versus controls ranged between 1.14 and 1.42, values similar to those for irrelevant probe variables used to reveal recall bias.

In contrast, the OR for clinically manifest IM in MS cases versus controls, corrected for demographic variables, was 2.22 (95% confidence interval 1.73 - 2.86; P < 0.001). The average age of onset of IM in the population of MSers (16.5 years) did not differ from controls (16.8 years). Their data confirm previous much smaller studies to show that the risk for MS is significantly enhanced by prior IM, and extend those previous data by showing that this association is far stronger than with other common childhood infections or afflictions.

BACKGROUND: Genetic and environmental factors have important roles in MS susceptibility. Several studies have attempted to correlate exposure to viral illness with the subsequent development of MS. Here in a population-based Canadian cohort, the researchers investigated the relationship between prior clinical infection or vaccination and the risk of MS.

METHODS: Using the longitudinal Canadian database, 14,362 MS index cases and 7,671 spouse controls were asked about history of measles, mumps, rubella, varicella (Chicken pox) and infectious mononucleosis as well as details about vaccination with measles, mumps, rubella, hepatitis B and influenza vaccines. Comparisons were made between cases and spouse controls.

RESULTS: Spouse controls and stratification by sex appear to correct for ascertainment bias because with a single exception we found no significant differences between cases and controls for all viral exposures and vaccinations. However, 699 cases and 165 controls reported a history of infectious mononucleosis (p < 0.001, corrected odds ratio 2.06, 95% confidence interval 1.71-2.48). Females were more aware of disease history than males (p < 0.001).

CONCLUSIONS: The data further confirms a reporting distortion between males and females. Historically reported measles, mumps, rubella (German Measles), varicella (Chicken pox) and vaccination for hepatitis B, influenza, measles, mumps and rubella are not associated with increased risk of MS later in life. A clinical history of infectious mononucleosis is conspicuously associated with increased MS susceptibility. These findings support studies implicating Epstein-Barr virus in MS disease susceptibility, but a co-association between MS susceptibility and clinically apparent infectious mononucleosis cannot be excluded.

"There have been many studies reporting the link between certain viruses and MS. But when looked at using larger sample sizes most viruses have fallen by the wayside. The exception appears to be Epstein Barr Virus (EBV) which causes glandular fever or infectious mononucleosis If you have glandular fever and got the virus in adolescence it increases your risk (using the data above about twice as likely) of developing MS. Search on the BLOG for EBV and infectious mononucleosis and there are loads of posts as a pet subject of Prof G."

CoI: Studies were my members of Team G or from the partners of people from Team G

In this meta-analysis we show that women who breastfeed were almost twice as likely not to have a post-partum relapse than woman would did not; in 8 prospective studies the odds ratio (OR) of having a relapse was 0.46 (0.30–0.70).

"This meta-analysis gives me confidence to tell woman MSers that breast feeding is a good thing and lowers your risk of having a relapse in the 6 month post-partum period by approximately 50% compared to the risk if you did not breast feed."

"Six months is also more than long enough to provide your child with the health benefits of breast feeding."

Friday, 25 May 2012

BACKGROUND: Restless legs syndrome (RLS) is a frequent neurological
disorder which is presented in idiopathic and secondary form. Idiopathic
RLS is associated with common genetic variants in four chromosomal
regions. Recently, multiple sclerosis (MS) was identified as a common
cause for secondary RLS. The aim of our study was to evaluate the
prevalence of RLS among Czech patients with MS and to further analyze
the impact of known genetic risk factors for RLS in patients with MS.

METHODS:
Each patient underwent a semi-structured interview. A patient was
considered to be affected by RLS if all four standard criteria had ever
been met in their lifetime. The sample was genotyped using 12 single
nucleotide polymorphisms within the four genomic regions, which were
selected according to the results of previous genome-wide association
studies.

RESULTS: A
total of 765 subjects with MS were included in the study and the
diagnosis of RLS was confirmed in 245 subjects (32.1%, 95%CI
28.7-35.4%). The genetic association study included 642 subjects; 203 MS
patients with RLS were compared to 438 MS patients without RLS. No
significant association with MEIS 1, BTBD9, and PTPRD gene variants was
found despite sufficient statistical power for the first two loci. There
was a trend for association with the MAP2K5/SCOR1 gene - the best model
for the risk allele was the recessive one (p nominal=0.0029, p
corrected for four loci and two models=0.023, odds ratio=1.60).

CONCLUSION:
We confirmed that RLS prevalence was high in patients with multiple
sclerosis, but this form did not share all genetic risk variants with
idiopathic (without an known cause) RLS.

We have posted on and described this subject recently so no need to comment on this again, but this shows further that restless leg syndrome is common with an occurance of about 30%.

Multiple sclerosis
(MS) is an inflammatory, autoimmune disease of the central nervous
system. The cause of MS is still unknown but epidemiological and
immunological studies have implicated Epstein-Barr virus (EBV), which
infects B cells, as a possible aetiological agent involved in disease. Of
particular interest is EBV latent membrane protein 2A (LMP2A) because
previous studies have demonstrated that LMP2A enhances the expansion and
differentiation of B cells upon antigen stimulation, revealing a
potential contribution of this protein in autoimmunity. Since B cells
are thought to contribute to MS, we examined the role of LMP2A in the
animal model experimental autoimmune encephalomyelitis (EAE). In this
model, transgenic mice in which B cells express LMP2A show increased
severity and incidence of disease. This difference was not due to
lymphocyte recruitment into the CNS or differences in T cell activation,
rather, we show that LMP2A enhances antigen presentation function

This report in scientific methods reports that a protein made by EBV augments neurological attack caused by enhancement of antigen presentation by B cells. However, the evidence that B cells are that important in early stages of EAE is rather lacking. Indeed you can get normal EAE in the complete absence of B cells as shown previously , although it has been shown that B cell activity can augment T cell-mediated autoimmunity.

This study reports on some odd findings and it
would be a very surprsing that increases severity of disease are
not associated with increased recruitment into the CNS. So when we look at the data, first thing to say they report using tests that are not correct for the data) and using the "smack you in the eye test", there looks to be no real difference. On closer look at the data they compare a mean
score on 2.7 verses 2.3 respectively , however with an incidence of 92% and 79%. This
means the scores of the affected animals are 2.9 and 2.9. If the clinical
scores are compared like for like you would not expect any
difference. They see a small difference but is it simply skewed by the
fact that less animals got disease in the transgenic than wild type-normal mouse. Abit of a Shania. Best stop there before I say too much.

Epstein-Barr virus (EBV) has been identified as a putative environmental trigger of multiple sclerosis
(MS), yet EBV's role in MS remains elusive. We utilized murine gamma
herpesvirus 68 (γHV-68), the murine homolog to EBV, to examine how
infection by a virus like EBV could enhance CNS autoimmunity. Mice
latently infected with γHV-68 developed more severe EAE including
heightened paralysis and mortality. Similar to MS, γHV-68EAE mice
developed lesions composed of CD4 and CD8 T cells, macrophages and loss
of myelin in the brain and spinal cord. Further, T cells from the CNS of
γHV-68 EAE mice were primarily Th1, producing heightened levels of
IFN-γ and T-bet accompanied by IL-17 suppression, whereas a Th17
response was observed in uninfected EAE mice. Clearly, γHV-68 latency
polarizes the adaptive immune response, directs a heightened CNS
pathology following EAE induction reminiscent of human MS and portrays a
novel mechanism by which EBV likely influences MS and other autoimmune
diseases.

life cycle of gamma HV-68

This report talks about mice infected with a virus gamma-HV-68.
It is suggested that this is a mouse equivalent of EBV, but does it
cause lymphoma, B cell immortalisation etc, etc. However according to
Wikipaedia, "MHV-68 is more closely related to the Kaposi's Sarcoma-associated herpesvirus (KSHV) than it is to the Epstein-Barr virus" If so the argument falls apart. So not so good EAE becomes good EAE when there is a viral infection. This latent virus does not re-activate and infect the CNS during EAE.

Just
so you know there have been studies on viruses and EAE for many years
including the first description of the use of the PL mouse strain. Unfortunately I can remember this paper from when it first came out...I am an old f**t :-)

PL/J
mice developed chronic relapsing experimental allergic
encephalomyelitis (EAE) after receiving syngeneic guinea pig basic
protein (GPBP)-immune lymph node cells or spleen cells which were
cultured in the presence of GPBP or the encephalitogenic N-terminal
peptide of GPBP. The presence of CD4+ cells and in vitro proliferation
in response to GPBP are required for the successful transfer.
Pathologically, adoptively-(T cell) transferred EAE in the virus-free PL/J
strain was characterized by an infiltration in the central nervous
system by small lymphocytes, followed by the appearance of macrophages,
and subsequently by primary demyelination. These findings were similar
to those previously observed in chronic relapsing EAE in SJL/J mice.
However, in some experiments pathologic examination of the spinal cord
showed large demyelinating lesions which were necrotic and infiltrated
with eosinophilic polymorphonuclear leucocytes. Sera from mice with this
pathology contained antibodies to murine hepatitis virus
and extensive search identified a few areas of coronavirus replication.
The pathology of autoimmune mediated demyelination may be altered in
the presence of coronavirus infection but the clinical pattern of EAE
expression did not differ between virus-free and coronavirus-infected mice.

Effects of treatment of MSers with IFN-β on elements of the antiviral immune response to herpesviruses were analysed in a longitudinal study. These investigators found significantly increased seroreactivity (antibodies) to EBV EBNA-1, and to VZV (Varicella-Zoster or chicken pox virus), in patients who did not respond to IFN-β therapy. We found no significant changes in seroreactivity to EBV EA (early antigen), or to HSV (herpes simplex virus, cold sores or genital herpes). For the same MS cohort, they have previously demonstrated significant decreases in seroreactivities to envelope antigens for the two human endogenous retroviruses HERV-H and HERV-W, closely linked to efficacy of therapy. They further searched for correlations between seroreactivities to EBV, HSV, and VZV, and levels of mannan-binding lectin (MBL), and MBL-associated serine protease 3. They found no such correlations. Their results are in accord with recent reports of increased seroreactivity to EBV EBNA-1, and to VZV in active MS, and support the herpesviruses EBV and VZV together with HERV-H/HERV-W and the antiviral immune response may play a role in MS development.

"Interferons are molecules that prevent viral replication; i.e. they are antivirals, which is why they were tried in MS. These results give us a clue to why interferons may work in MS and what the triggers are that cause MS. This is why we are so interested in testing anti-viral agents in MS. Please see the page on the blog on the Charcot Project."

This study characterizes a new nationwide incident cohort of MS from the US military-veteran population. This cohort provides an update to the only other US nationwide incidence study of MS performed during the 1970s. Medical records and data from the Department of Defense and Department of Veterans Affairs for cases of MS who served in the military between 1990, the start of the Gulf War era, and 2007 and who were service-connected for this disorder by the Department of Veterans Affairs from 1990 on, were reviewed. A total of 2691 MSers were confirmed as having MS: 2288 definite, 190 possible, 207 clinically isolated syndrome and six neuromyelitis optica. Overall racial categories were White, Black and other, which included all Hispanics. There were 1278 White males and 556 females; 360 Black males and 296 females; and 200 others, 153 (77%) of whom were Hispanic. Mean age at onset of 30.7 years did not differ significantly by race or sex. Age at onset was 17–50 years in 99%, the same age range as 99% of the military. Average annual age specific (age 17–50 years) incidence rates per 100 000 for the entire series were 9.6 with 95% confidence interval of 9.3–10.0. Rates for Blacks were highest at 12.1 with confidence interval 11.2–13.1, Whites were 9.3 (interval 8.9–9.8) and others 6.9 (interval 6.0–7.9). For 83 Hispanics defined for 2000–07, the rate was 8.2 (interval 6.5–10.1). Much smaller numbers gave rates of 3.3 for Asian/Pacific Islanders and 3.1 for native Americans. Rates by sex for Whites were 7.3 and 25.8 male and female, respectively, for Blacks 8.4 and 26.3, and for Hispanics 6.6 and 17.0. Rates by service were high for Air Force (10.9) and Army (10.6), medium for Navy (9.1) and Coast Guard (7.9), and low for Marines (5.3). Relative risk of MS was 3.39 female:male and 1.27 Black:White. These new findings indicate that females of all races now have incidence rates for MS some three times those of their male counterparts and that among these groups, Blacks have the highest and others (probably including Hispanics) the lowest incidence rates regardless of sex or service. The low rate for Marines is unexplained. This Gulf War era multiple sclerosis cohort provides a unique resource for further study.

MS becomes more black and white

"We have been saying that MS has become a predominantly female disease, which is supported by this study of American miltary personnel. The sex ratio of female to male is over 3:1. The astonishing thing is that the ratio of black to white MSers has reached parity and in fact is exceeding the amount of MS in white military personel.This has changed from the Second World war era when the ratio of white males to black males was 2 to 1, now it is one to one in the Gulf War Era (1990 to 2007)."

"The table from the paper shows the ratio of MS relative to white males in US forces over history."

"The rate of smoking has probably dropped in this cohort of people over this period, but the data further indicate the importance of environmental factors in determining whether MS occurs. It suggests that by modifying the environment we can prevent MS from occurring in some people. MS clearly does not discriminate; although saying that it clearly favours woman."

"The person who finds out why MS is increasing so rapidly in woman will pin down the cause of MS."

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